Since the discovery of the first histone lysine specific demethylase LSD1/KDM1a, histone lysine demethylation has emerged as an epigenetic paradigm (Shi et al., 2004). So far, over 20 histone lysine demethylases (KDMs) have been characterized, belonging to either the FAD-dependent LSD or the Fe2+ and α-ketoglutarate-dependent Jumonji C-terminal domain (JmjC) family (Allis et al., 2007; Bernstein et al., 2007; Chen et al., 2006b; Klose et al., 2006; Kubicek and Jenuwein, 2004; Rice and Allis, 2001; Ruthenburg et al., 2007). Genetic, biochemical and functional studies further indicate that these KDMs play a role in a wide range of biological processes, including gene expression, cell growth, differentiation, development and disease pathogenesis (Bhaumik et al., 2007; Egger et al., 2004; Esteller, 2008; Nottke et al., 2009; Shi, 2007). Abrogated expression or enzymatic activity of histone demethylases has been implicated in human diseases such as cancer (Chi et al., 2010; Esteller, 2008; Smith et al., 2007). Therefore, deciphering the regulatory mechanisms of histone demethylases is important for understanding their biological and pathophysiological functions (Chen et al., 2007; Chen et al., 2006b; Horton et al., 2010; Shi, 2007).
For example it is important to understand how the activity of KDMs is regulated (Chen et al., 2007; Chen et al., 2006b; Horton et al., 2010; Lan et al., 2008; Wilson, 2007). It has been found that many KDMs, while active on synthetic peptides or core histone substrates, exhibit very weak or no detectable activity on nucleosomal substrates in vitro. However, when transfected into cells robust activity on chromatin can be detected, suggesting the existence of additional cofactors required for full activity (Shi et al., 2004; Tahiliani et al., 2007).
We, and others, have identified CoREST as a cofactor required for LSD1/KDM1a action on nucleosomal substrates (Lee et al., 2005; Shi et al., 2005), representing the first breakthrough toward understanding how KDM activity is regulated. However, the molecular details underlying the cofactor-enhanced demethylase activity of LSD1 remain elusive (Forneris et al., 2007; Yang et al., 2006). Moreover, the cofactor activity of CoREST is highly specific, only facilitating demethylation of nucleosomal substrates by LSD1 but not any other KDMs. Further investigation is required to determine if cofactor-modulation is a general mechanism for the regulation of KDM functions. In particular, there are two areas to be addressed: first, whether different cofactors exist for other histone demethylases; and second, the molecular mechanism(s) employed by such cofactors to facilitate histone demethylase activity.
Answers to these questions would provide novel ways of treating diseases associated with defects resulting in dysfunction of these mechanisms.